Authors: Massimo Zucchetti Katiuscia Bonezzi Roberta Frapolli Federica Sala Patrizia Borsotti Monique Zangarini Esteban Cvitkovic Kay Noel Paolo Ubezio Raffaella Giavazzi Maurizio D’Incalci Giulia Taraboletti
Publish Date: 2013/08/24
Volume: 72, Issue: 4, Pages: 879-887
Abstract
After 5 mg/kg iv OTX008 achieved plasma Cmax of 1439 μg/mL distributed rapidly and was eliminated with a halflife of 314 h Tumor OTX008 Cmax 165 μg/g 176 μM achieved at 05 h remained high at 24 h 0516 μg/g 055 μM with AUC of 1576 μg/gh OTX008 accumulated in the tumor after repeated administrations achieving a concentration of 23 μM compatible with the concentrations active in vitro OTX008 5 mg/kg iv every other day for 3 weeks inhibited the in vivo growth of A27801A9 whereas U87MG was not sensitive In vitro OTX008 affected endothelial cell proliferation motility invasiveness and cord formation Tumor cell proliferation was also inhibited with differences in sensitivity among cell lines IC50 from 1 to 190 μM OTX008 potentiated the activity of the tyrosine kinase inhibitor sunitinib on A27801A9 in vivo and in vitro where the combination showed synergistic endothelial cells and additive A27801A9 antiproliferative activity indicating that the combination targets both the tumor and vascular compartments
Keywords: